REDUCTION OF HEAT-SHOCK-PROTEIN-70 AFTER PROLONGED TREATMENT WITH RETINOIDS - BIOLOGICAL AND CLINICAL IMPLICATIONS

Heat shock proteins (HSPs) are a group of highly conserved polypeptide s involved in cellular response to heat or other physical or chemical stresses. It has been recently reported that HSPs could play a role in cellular differentiation. In this study we have evaluated, by a cytof luorimetric method, the presence of HSP-70 in HL-60 cells during treat ment with all-trans retinoic acid (ATRA), g-cis retinoic acid (g-cis R A), and 13-cis retinoic acid (13-cis RA). After 1 and 3 days of incuba tion at 10(-7) M, HSP-70 did not show any Variation compared to contro l; prolonging the exposure, together with the appearance of cellular d ifferentiation along the granulocytic pathway and apoptosis, a progres sive decrease of HSP-70 was observed that, after 8 days of treatment, was reduced by 40% with ATRA and by 28% with 9-cis RA compared to untr eated samples, while only minimal changes were evident by incubating t he cells with 13-cis RA, Reduction of HSP-70 was not associated with d ecreased protein synthesis, as demonstrated by [H-3] leucine incorpora tion. Double labeling with propidium iodide showed a decrease in HSP-7 0 in all the phases of the cell cycle concomitant with a reduced perce ntage of cycling cells in ATRA-treated samples. Dot blot and Northern blot analysis demonstrated no change in HSP-70 mRNA after retinoid tre atment, thus suggesting a post-transcriptional regulation of the pheno menon. This reduced production of HSP-70 caused by ATRA and by g-cis R A, though to a lesser extent, could render the cells more sensitive to cytotoxic agents and could provide the rationale for the efficacy of ATRA + chemotherapy combinations. (C) 1997 Wiley-Liss, Inc.